New Imaging Agent Aids in Parkinson's Diagnosis

The Food and Drug Administration’s recent approval of the dopamine transporter radiotracer DaTscan (ioflupane I-123 injection) provides clinicians with a much-needed diagnostic tool for patients with questionable parkinsonian symptoms and could lead to earlier diagnosis of Parkinson’s disease and initiation of therapies to slow or halt disease progression.

GE Healthcare’s DaTscan is a radiolabeled compound that binds to dopamine transporter (DaT) protein, allowing for visualization of the distribution and relative amount of DaT in the striata using SPECT (single-photon emission computed tomography) imaging. The radiotracer allows neurologists to evaluate neurodegenerative movement disorders, such as idiopathic Parkinson’s disease (PD), and may be used as an adjunct to other diagnostic tools to help differentiate essential tremor from tremor resulting from parkinsonian syndromes. DaTscan is the first such imaging agent to be approved in the United States.

Dr. Kenneth Marek, president of the Institute for Neurodegenerative Disorders in New Haven, Conn., said DaT imaging is an objective measure that can provide more evidence about whether a patient has a dopamine deficit in the brain. "There is a little bit of a leap from ‘yes, you have a dopamine deficit in your brain’ to ‘yes, you have Parkinson’s disease’ but it’s not a very [big] leap."

Neurologists already know how much DaT to expect in healthy individuals, depending on age. "Typically, if an individual has lost more than about a half of their [expected] dopamine transporters, that would be very consistent with Parkinson’s disease," said Dr. Marek. DaTscan will provide a visual analysis of the amount. "Nuclear medicine physicians, who are very familiar with this type of work, will simply look at the images and compare them with healthy images."

DaTscan might be of greater diagnostic value to subsets of patients. "Not everyone will require a test like this," Dr. Marek said in an interview. For example, DaT scanning would not be useful for a patient who has more advanced disease at presentation or those with very typical symptoms early on.

However, it can be helpful in patients who "have questionable symptoms or who are very early in their disease or who have intermittent symptoms. ... It’s really for individuals about whom there is substantial uncertainty of diagnosis," Dr. Marek explained.

Although current clinical uses of brain imaging with DaTscan are reason enough for patients and neurologists to be excited about its approval, the real potential is in the research arena.

"By the time someone with symptoms ends up presenting to their physician, they’ve probably lost on the order of 50%-60% of their dopamine activity, as one would measure it using this imaging tool," Dr. Marek said.

It follows that early in PD, there is a time when a patient has lost some DaT but has no symptoms. "It turns out that this imaging technique is very robust in being able to distinguish between individuals who are normal and those who actually have early Parkinson’s disease."

There are already a number of studies underway to identify those individuals. One way to do this is to evaluate relatives of individuals with PD – particularly people who have a known genetic disorder. "You could theoretically follow these individuals before they have Parkinson’s symptoms; indeed, we are actually doing exactly that study," said Dr. Marek. The study is sponsored by the Michael Fox Foundation.

Another way to identify people before they develop Parkinson’s symptoms is through their loss of the sense of smell, which can appear even before more typical motor symptoms. In fact, Dr. Marek and his coinvestigators are conducting another study using a scratch and sniff test.

From this group, the researchers have identified individuals with poor sense of smell and those with a good sense of smell. Both groups have undergone imaging, so that the researchers can identify the participants who have a poor sense of smell and abnormal brain imaging but do not have any Parkinson’s symptoms.

"The idea is to follow those people to see if this [imaging] would help us ultimately screen for Parkinson’s disease, with the idea that eventually this would be the group that you’d want to identify for treatment," Dr. Marek said. "From a research perspective, this is the most exciting use of this imaging and it takes advantage of the fact that you can identify individuals before they have symptoms."

Of course, without disease-modifying drugs, the ability to identify patients before symptoms appear is of limited use. However, DaT imaging will likely play a big role in the development of such therapies.

The Parkinson Progression Marker Initiative (sponsored by the Michael J. Fox Foundation) is one such research initiative that is aimed at understanding how brain imaging and other types of biomarkers can be used in drug development.

"We look at Parkinson’s disease as a whole because we don’t know how to separate it, but it’s very likely that within Parkinson’s disease there are some individuals who respond to one drug and not another, and certainly there are individuals who progress more rapidly than others," said Dr. Marek.

"This would be another way to focus treatment more effectively on those who would be more likely to respond to it, if you could identify different biomarkers to identify these subgroups."

There have been other DaT-related tracers that have been used for research over the last 12-15 years in the United States, but it has been difficult to get FDA approval for such agents, because the bar for approval from the FDA’s perspective was to demonstrate that DaT agents were useful as diagnostic tools for Parkinson’s disease, Dr. Marek said in an interview.

However, the agency’s approach to imaging agents has changed in recent years. Manufacturers can now seek indications for imaging agents in four categories: delineation of structure; disease or pathology detection or assessment; functional, physiological, or biochemical assessment; and diagnostic or therapeutic patient management.

DaTscan is indicated for striatal dopamine transporter visualization using SPECT brain imaging to assist in the evaluation of adult patients with suspected parkinsonian syndromes. "That is to say that it is not necessarily a diagnostic tool for Parkinson’s disease, but that it measures dopamine transporter density in the brain and that’s its primary indication," said Dr. Marek. "That distinction enabled the FDA to move ahead more rapidly." DaTscan has been available in Europe since 2000.

Another problem related to its approval is that DaTscan is a derivative of cocaine, so it is classified in the United States as a schedule II drug under the Controlled Substances Act. Radiologists and nuclear medicine physicians working with the tracer will have to be licensed for schedule II drugs by the Drug Enforcement Administration.

Dr. Marek is a consultant for GE Healthcare.

The Food and Drug Administration’s recent approval of the dopamine transporter radiotracer DaTscan (ioflupane I-123 injection) provides clinicians with a much-needed diagnostic tool for patients with questionable parkinsonian symptoms and could lead to earlier diagnosis of Parkinson’s disease and initiation of therapies to slow or halt disease progression.

GE Healthcare’s DaTscan is a radiolabeled compound that binds to dopamine transporter (DaT) protein, allowing for visualization of the distribution and relative amount of DaT in the striata using SPECT (single-photon emission computed tomography) imaging. The radiotracer allows neurologists to evaluate neurodegenerative movement disorders, such as idiopathic Parkinson’s disease (PD), and may be used as an adjunct to other diagnostic tools to help differentiate essential tremor from tremor resulting from parkinsonian syndromes. DaTscan is the first such imaging agent to be approved in the United States.

Dr. Kenneth Marek, president of the Institute for Neurodegenerative Disorders in New Haven, Conn., said DaT imaging is an objective measure that can provide more evidence about whether a patient has a dopamine deficit in the brain. "There is a little bit of a leap from ‘yes, you have a dopamine deficit in your brain’ to ‘yes, you have Parkinson’s disease’ but it’s not a very [big] leap."

Neurologists already know how much DaT to expect in healthy individuals, depending on age. "Typically, if an individual has lost more than about a half of their [expected] dopamine transporters, that would be very consistent with Parkinson’s disease," said Dr. Marek. DaTscan will provide a visual analysis of the amount. "Nuclear medicine physicians, who are very familiar with this type of work, will simply look at the images and compare them with healthy images."

DaTscan might be of greater diagnostic value to subsets of patients. "Not everyone will require a test like this," Dr. Marek said in an interview. For example, DaT scanning would not be useful for a patient who has more advanced disease at presentation or those with very typical symptoms early on.

However, it can be helpful in patients who "have questionable symptoms or who are very early in their disease or who have intermittent symptoms. ... It’s really for individuals about whom there is substantial uncertainty of diagnosis," Dr. Marek explained.

Although current clinical uses of brain imaging with DaTscan are reason enough for patients and neurologists to be excited about its approval, the real potential is in the research arena.

"By the time someone with symptoms ends up presenting to their physician, they’ve probably lost on the order of 50%-60% of their dopamine activity, as one would measure it using this imaging tool," Dr. Marek said.

It follows that early in PD, there is a time when a patient has lost some DaT but has no symptoms. "It turns out that this imaging technique is very robust in being able to distinguish between individuals who are normal and those who actually have early Parkinson’s disease."

There are already a number of studies underway to identify those individuals. One way to do this is to evaluate relatives of individuals with PD – particularly people who have a known genetic disorder. "You could theoretically follow these individuals before they have Parkinson’s symptoms; indeed, we are actually doing exactly that study," said Dr. Marek. The study is sponsored by the Michael Fox Foundation.

Another way to identify people before they develop Parkinson’s symptoms is through their loss of the sense of smell, which can appear even before more typical motor symptoms. In fact, Dr. Marek and his coinvestigators are conducting another study using a scratch and sniff test.

From this group, the researchers have identified individuals with poor sense of smell and those with a good sense of smell. Both groups have undergone imaging, so that the researchers can identify the participants who have a poor sense of smell and abnormal brain imaging but do not have any Parkinson’s symptoms.

"The idea is to follow those people to see if this [imaging] would help us ultimately screen for Parkinson’s disease, with the idea that eventually this would be the group that you’d want to identify for treatment," Dr. Marek said. "From a research perspective, this is the most exciting use of this imaging and it takes advantage of the fact that you can identify individuals before they have symptoms."

Of course, without disease-modifying drugs, the ability to identify patients before symptoms appear is of limited use. However, DaT imaging will likely play a big role in the development of such therapies.

The Parkinson Progression Marker Initiative (sponsored by the Michael J. Fox Foundation) is one such research initiative that is aimed at understanding how brain imaging and other types of biomarkers can be used in drug development.

"We look at Parkinson’s disease as a whole because we don’t know how to separate it, but it’s very likely that within Parkinson’s disease there are some individuals who respond to one drug and not another, and certainly there are individuals who progress more rapidly than others," said Dr. Marek.

"This would be another way to focus treatment more effectively on those who would be more likely to respond to it, if you could identify different biomarkers to identify these subgroups."

There have been other DaT-related tracers that have been used for research over the last 12-15 years in the United States, but it has been difficult to get FDA approval for such agents, because the bar for approval from the FDA’s perspective was to demonstrate that DaT agents were useful as diagnostic tools for Parkinson’s disease, Dr. Marek said in an interview.

However, the agency’s approach to imaging agents has changed in recent years. Manufacturers can now seek indications for imaging agents in four categories: delineation of structure; disease or pathology detection or assessment; functional, physiological, or biochemical assessment; and diagnostic or therapeutic patient management.

DaTscan is indicated for striatal dopamine transporter visualization using SPECT brain imaging to assist in the evaluation of adult patients with suspected parkinsonian syndromes. "That is to say that it is not necessarily a diagnostic tool for Parkinson’s disease, but that it measures dopamine transporter density in the brain and that’s its primary indication," said Dr. Marek. "That distinction enabled the FDA to move ahead more rapidly." DaTscan has been available in Europe since 2000.

Another problem related to its approval is that DaTscan is a derivative of cocaine, so it is classified in the United States as a schedule II drug under the Controlled Substances Act. Radiologists and nuclear medicine physicians working with the tracer will have to be licensed for schedule II drugs by the Drug Enforcement Administration.

Dr. Marek is a consultant for GE Healthcare.

The Food and Drug Administration’s recent approval of the dopamine transporter radiotracer DaTscan (ioflupane I-123 injection) provides clinicians with a much-needed diagnostic tool for patients with questionable parkinsonian symptoms and could lead to earlier diagnosis of Parkinson’s disease and initiation of therapies to slow or halt disease progression.

GE Healthcare’s DaTscan is a radiolabeled compound that binds to dopamine transporter (DaT) protein, allowing for visualization of the distribution and relative amount of DaT in the striata using SPECT (single-photon emission computed tomography) imaging. The radiotracer allows neurologists to evaluate neurodegenerative movement disorders, such as idiopathic Parkinson’s disease (PD), and may be used as an adjunct to other diagnostic tools to help differentiate essential tremor from tremor resulting from parkinsonian syndromes. DaTscan is the first such imaging agent to be approved in the United States.

Dr. Kenneth Marek, president of the Institute for Neurodegenerative Disorders in New Haven, Conn., said DaT imaging is an objective measure that can provide more evidence about whether a patient has a dopamine deficit in the brain. "There is a little bit of a leap from ‘yes, you have a dopamine deficit in your brain’ to ‘yes, you have Parkinson’s disease’ but it’s not a very [big] leap."

Neurologists already know how much DaT to expect in healthy individuals, depending on age. "Typically, if an individual has lost more than about a half of their [expected] dopamine transporters, that would be very consistent with Parkinson’s disease," said Dr. Marek. DaTscan will provide a visual analysis of the amount. "Nuclear medicine physicians, who are very familiar with this type of work, will simply look at the images and compare them with healthy images."

DaTscan might be of greater diagnostic value to subsets of patients. "Not everyone will require a test like this," Dr. Marek said in an interview. For example, DaT scanning would not be useful for a patient who has more advanced disease at presentation or those with very typical symptoms early on.

However, it can be helpful in patients who "have questionable symptoms or who are very early in their disease or who have intermittent symptoms. ... It’s really for individuals about whom there is substantial uncertainty of diagnosis," Dr. Marek explained.

Although current clinical uses of brain imaging with DaTscan are reason enough for patients and neurologists to be excited about its approval, the real potential is in the research arena.

"By the time someone with symptoms ends up presenting to their physician, they’ve probably lost on the order of 50%-60% of their dopamine activity, as one would measure it using this imaging tool," Dr. Marek said.

It follows that early in PD, there is a time when a patient has lost some DaT but has no symptoms. "It turns out that this imaging technique is very robust in being able to distinguish between individuals who are normal and those who actually have early Parkinson’s disease."

There are already a number of studies underway to identify those individuals. One way to do this is to evaluate relatives of individuals with PD – particularly people who have a known genetic disorder. "You could theoretically follow these individuals before they have Parkinson’s symptoms; indeed, we are actually doing exactly that study," said Dr. Marek. The study is sponsored by the Michael Fox Foundation.

Another way to identify people before they develop Parkinson’s symptoms is through their loss of the sense of smell, which can appear even before more typical motor symptoms. In fact, Dr. Marek and his coinvestigators are conducting another study using a scratch and sniff test.

From this group, the researchers have identified individuals with poor sense of smell and those with a good sense of smell. Both groups have undergone imaging, so that the researchers can identify the participants who have a poor sense of smell and abnormal brain imaging but do not have any Parkinson’s symptoms.

"The idea is to follow those people to see if this [imaging] would help us ultimately screen for Parkinson’s disease, with the idea that eventually this would be the group that you’d want to identify for treatment," Dr. Marek said. "From a research perspective, this is the most exciting use of this imaging and it takes advantage of the fact that you can identify individuals before they have symptoms."

Of course, without disease-modifying drugs, the ability to identify patients before symptoms appear is of limited use. However, DaT imaging will likely play a big role in the development of such therapies.

The Parkinson Progression Marker Initiative (sponsored by the Michael J. Fox Foundation) is one such research initiative that is aimed at understanding how brain imaging and other types of biomarkers can be used in drug development.

"We look at Parkinson’s disease as a whole because we don’t know how to separate it, but it’s very likely that within Parkinson’s disease there are some individuals who respond to one drug and not another, and certainly there are individuals who progress more rapidly than others," said Dr. Marek.

"This would be another way to focus treatment more effectively on those who would be more likely to respond to it, if you could identify different biomarkers to identify these subgroups."

There have been other DaT-related tracers that have been used for research over the last 12-15 years in the United States, but it has been difficult to get FDA approval for such agents, because the bar for approval from the FDA’s perspective was to demonstrate that DaT agents were useful as diagnostic tools for Parkinson’s disease, Dr. Marek said in an interview.

However, the agency’s approach to imaging agents has changed in recent years. Manufacturers can now seek indications for imaging agents in four categories: delineation of structure; disease or pathology detection or assessment; functional, physiological, or biochemical assessment; and diagnostic or therapeutic patient management.

DaTscan is indicated for striatal dopamine transporter visualization using SPECT brain imaging to assist in the evaluation of adult patients with suspected parkinsonian syndromes. "That is to say that it is not necessarily a diagnostic tool for Parkinson’s disease, but that it measures dopamine transporter density in the brain and that’s its primary indication," said Dr. Marek. "That distinction enabled the FDA to move ahead more rapidly." DaTscan has been available in Europe since 2000.

Another problem related to its approval is that DaTscan is a derivative of cocaine, so it is classified in the United States as a schedule II drug under the Controlled Substances Act. Radiologists and nuclear medicine physicians working with the tracer will have to be licensed for schedule II drugs by the Drug Enforcement Administration.

Dr. Marek is a consultant for GE Healthcare.